Heterocycle-substituted benzenemethanamine derivatives

ABSTRACT

The present invention is concerned with antiretroviral (e.g. anti-HIV-1)compounds having the formula ##STR1## wherein R 1  and R 2  each independently are halo or methyl; R 3  is hydrogen, halo, nitro or trifiuoromethyl; R 4  is trifiuoromethyl or methylcarbonyl; or a radical --C(═X)--NR 5  R 6  wherein X is O or S, and R 5  and R 6  each independently are hydrogen or C 1-4  alkyl; or a radical -Alk-R 7 , wherein Alk is C 1-4  alkanediyl; and R 7  is hydrogen or hydroxy; Het is a heterocyclic radical of formula: ##STR2## Pharmaceutical compositions containing said compounds of formula (I) and processes of preparing said compounds and compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of application Ser. No. 08/240,737,filed May 12, 1994, now U.S. Pat. No. 5,480,997 is of PCT ApplicationNo. PCT/EP 92/02993, filed Dec. 22, 1992, published as WO93/13069, Jul.8, 1993, which claims priority from EPO application Serial No.91,203.431.1, filed Dec. 30, 1991.

BACKGROUND OF THE INVENTION

In U.S. Pat. No. 4,246,429 there are described a number ofbenzeneacetamides and thioamides being useful as intermediates in thepreparation of phytopharmaceutical compounds. Unexpectedly, it has nowbeen found that some analogous heterocyclic compounds effectivelyinhibit the replication of HIV and consequently may be useful for thetreatment of individuals infected by HIV, in particular HIV-1.

DESCRIPTION OF THE INVENTION

The present invention is concerned with compounds having the formula##STR3## the pharmaceutically acceptable acid addition salt forms andthe stereochemically isomeric forms thereof, wherein

R¹ and R² each independently are halo or methyl;

R³ is hydrogen, halo, nitro or trifluoromethyl;

R⁴ is

trifluoromethyl or methylcarbonyl; or

a radical --C(═X)--NR⁵ R⁶ wherein X is O or S, and

R⁵ and R⁶ each independently are hydrogen or C₁₋₄ alkyl; or

a radical -Alk-R⁷, wherein Alk is C₁₋₄ alkanediyl; and

R⁷ is hydrogen or hydroxy;

Het is a heterocyclic radical of formula: ##STR4## wherein R⁸ is C₁₋₄alkyl or hydrogen;

R⁹ and R¹⁰ each independently are hydrogen, C₁₋₄ alkylcarbonyl, C₁₋₄alkyl, halo or nitro;

R¹¹ is hydrogen, nitro, halo or C₁₋₄ alkyl;

R¹² is hydrogen, C₁₋₄ alkyl or C₁₋₄ alkylcarbonyl;

R¹³ is hydrogen or hydroxy;

R¹⁴ is hydrogen, nitro, cyano, halo, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₁₋₄alkylcarbonyl;

R¹⁵ is hydrogen, nitro, cyano, halo, C₁₋₄ alkyl, C₁₋₄ alkyloxy, C₁₋₄alkylcarbonyl; or

R¹⁴ and R¹⁵ taken together form C₃₋₄ alkanediyl;

R¹⁶ is hydrogen, C₁₋₄ alkylcarbonyl, nitro or halo; and

in the heterocyclic radicals of formula (a), (c), (d) or (e) a nitrogenatom can optionally be oxidized.

The compounds of formula (I) wherein at least one of R⁵ and R⁶ ishydrogen or wherein R¹³ is hydroxy may also exist in their tautomericform. Said form, although not explicitly indicated hereinabove, isintended to be included within the scope of the present invention.

In the foregoing definitions and hereinafter the term halo definesfluoro, chloro, bromo and iodo; C₁₋₄ alkyl defines straight and branchedsaturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as,for example, .methyl, ethyl, propyl, 1-methylethyl, butyl,1-methylpropyl, 2-methylpropyl and 1,1-dimethylethyl; C₁₋₄ alkanediyldefines bivalent straight or branch chained hydrocarbon radicalscontaining from 1 to 4 carbon atoms such as, for example,1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the branched isomersthereof, C₃₋₄ alkanediyl defines those C₁₋₄ alkanediyl radicals whichcontain 3 or 4 carbon atoms such as 1,3-propanediyl or 1,4-butanediyl;C₁₋₄ alkyloxy defines straight and branch chained alkyloxy radicals suchas methoxy, ethoxy, propyloxy, butyloxy and the like; C₁₋₆ alkyloxydefines said C₁₋₄ alkyloxy radicals and the higher homologues thereofcontaining 5 or 6 carbonatoms, such as pentyloxy, hexyloxy; C₁₋₄alkylcarbonyl defines straight and branch chained acyl radicals such asmethylcarbonyl, ethylcarbonyl, propylcarbonyl, butylcarbonyl and thelike.

Pharmaceutically acceptable addition salts as mentioned hereinabovecomprise the therapeutically active non-toxic addition salt forms whichthe compounds of formula (I) are able to form. Said salt forms canconveniently be obtained by treating the base form of the compounds offormula (I) with appropriate acids such as inorganic acids, for example,hydrohalic acid, e.g. hydrochloric, hydrobromic and the like acids,sulfuric acid, nitric acid, phosphoric acid and the like; or organicacids, such as, for example, acetic, propanoic, hydroxyacetic,2-hydroxypropanoic, 2-oxopropanoic, propanedioic, butanedioic,(Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic,2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic,methanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic,cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and thelike acids. Conversely the salt form can be converted by treatment withalkali into the free base form. The term addition salt also comprisesthe hydrates and solvent addition forms which the compounds of formula(I) are able to form. Examples of such forms are e.g. hydrates,alcoholates and the like.

The term "stereochemically isomeric forms" as used hereinbefore definesall the possible isomeric forms which the compounds of formula (I) maypossess. Unless otherwise mentioned or indicated, the chemicaldesignation of compounds denotes the mixture of all possiblestereochemically isomeric forms, said mixtures containing alldiastereomers and enantiomers of the basic molecular structure.Stereochemically isomeric forms of the compounds of formula (I) areobviously intended to be embraced within the scope of this invention.

An interesting group of compounds are those compounds of formula (I)wherein R¹ and R² are halo; R³ is hydrogen or halo; R⁴ is a radical--C(═O)--NR⁵ R⁶ or a radical -Alk-R⁷, wherein R⁷ is hydrogen.

More interesting compounds are those interesting compounds wherein Hetis a heterocyclic radical

of formula (a), wherein

R⁸ is C₁₋₄ alkyl;

R⁹ and R¹⁰ each independently are C₁₋₄ alkyl or nitro;

of formula (c), wherein

R¹² is C₁₋₄ alkylcarbonyl;

of formula (d), wherein

R¹³ is hydrogen or hydroxy;

R¹⁴ is hydrogen, nitro, cyano, C₁₋₄ alkylcarbonyl;

R¹⁵ is hydrogen; or R¹⁴ and R¹⁵ taken together form C₃₋₄ alkanediyl;

of formula (e), wherein

R¹⁶ is C₁₋₄ alkylcarbonyl.

Particularly interesting compounds are those more interesting compoundwherein R⁴ is a radical C(═O)NH₂ or methyl and Het is3-cyano-2-pyridinyl, 3-nitro-2-pyridinyl,2-ethyl-5-methyl-4-nitro-2H-pyrazol-3-yl, 2-nitro-3-thienyl,3-acetyl-5,6,7,8-tetrahydro-4-quinolinyl, 3-acetyl-2-pyridinyl,3-acetyl-2-pyrazinyl, 1,2-dihydro-2-oxo-3-pyridinyl.

Preferred compounds are:

2,6-dichloro-α-[(3-cyano-2-pyridinyl)amino]benzeneacetamide,

2,6-dichloro-α-[(3-nitro-2-pyridinyl)amino]benzeneacetamide,

2,6-dichloro-α-[(2-ethyl-5-methyl-4-nitro-2H-pyrazol-3-yl)amino]benzeneacetamide,

1-[2-[[1-(2,6-dichlorophenyl)ethyl]amino]-3-pyridinyl]ethanone,

N-[1-(2,6-dichlorophenyl)ethyl]-3-nitro-2-pyridinamine,

2,6-dichloro-α-[(1,2-dihydro-2-oxo-3-pyridinyl)amino]benzeneacetamide

α-[(3-acetyl-2-pyrazinyl)amino]-2,6-dichlorobenzeneacetamide,

1-[3-[[1-(2,6-dichlorophenyl)ethyl]amino]-2-pyrazinyl]ethanone, thepharmaceutically acceptable acid addition salt forms and thestereochemically isomeric forms thereof.

The compounds of formula (I) can be prepared by reacting an intermediateof formula (II) with an appropriate heterocyclic derivative of formula(III). ##STR5##

In formula (III), W¹ represents a reactive leaving group such as, forexample, halo, preferably chloro or bromo; C₁₋₄ alkyloxy; aryloxy; asulfonyloxy group, e.g. methanesulfonyloxy, 4-methylbenzenesulfonyloxyand the like; or a C₁₋₆ alkylthio. The reaction can be performedfollowing art-known procedures, preferably at an elevated temperatureand in particular at the reflux temperature of the reaction mixture,whereby an excess of one of the reactants can be used as solvent; oroptionally in admixture with an appropriate solvent such as, forexample, water, a dipolar aprotic solvent, e.g. N,N-dimethylacetamide;an ether, e.g. tetrahydrofuran; an alcohol, e.g. ethanol; an aromaticsolvent, e.g. methylbenzene and the like and mixtures of such solvents.An appropriate base such as, for example, an alkali metal or an earthalkaline metal carbonate, hydrogen carbonate, hydroxide, alkoxide,hydride or amide, or an organic base such as, for example, an amine,e.g. N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine, pyridineand the like, may optionally be used to pick up the acid which is formedduring the course of the reaction. Additionally, it may be advantageousto conduct said reaction under an inert atmosphere such as, for example,oxygen-free argon or nitrogen gas. Phase transfer catalysis conditionsmay equally be employed in the above reaction.

In this and the following preparations, the reaction products may beisolated from the reaction mixture and, if necessary, further purifiedaccording to methodologies generally known in the art such as, forexample, extraction, distillation, crystallization, trituration andchromatography.

The compounds of formula (I) can also be prepared by alkylating anappropriate heterocyclic derivative of formula (V) or a salt thereof,with an alkylating reagent of formula (IV) following art-knownN-alkylation procedures. In formula (IV), W² represents a reactiveleaving group such as, for example, halo, e.g. chloro, bromo or iodo, asulfonyloxygroup, e.g. methanesulfonyloxy, 4-methylbenzenesulfonyloxyand the like reactive leaving groups. ##STR6##

Said N-alkylation reaction can conveniently be carried out followingart-known procedures by stirring the reactants in an appropriatesolvent, optionally in admixture with a base.

The compounds of formula (I) wherein R⁴ is a radical --C(═X)--NR⁵ R⁶,wherein X is O or S, R⁵ and R⁶ are hydrogen; said compounds beingrepresented by formula (I-a) when X is O and by formula (I-b) when X isS, can be prepared by reacting a nitrile of formula (VI), with a reagentH₂ X (VII), namely water or hydrogen suede, under appropriateconditions. ##STR7##

The hydrolysis of the nitrile (VI) to the corresponding amide (I-a), caneasily be carried out following art-known procedures. Preferably saidhydrolysis is carried out at room temperature or low temperatures suchas, for example, between 0° C. and room temperature, in a concentratedstrong acid, e.g. concentrated sulfuric acid, hydrochloric acid,hydrobromic acid and the like, optionally in the presence of a smallamount of water. Alternatively the nitrile of formula (VI) can behydrolyzed by stirring it in an appropriate solvent such as, forexample, an alcohol, e.g. ethanol, in the presence of hydrogen peroxideand an appropriate base such as, for example, an alkali metal hydroxide,e.g. sodium hydroxide.

The nitrile (VI) can conveniently be converted into the thioamide (I-b)by reaction with hydrogen sulfide in an appropriate solvent, e.g.pyridine, a mono-, di- or trimethylated pyridine and the like solvents,and in the presence of an appropriate base such as an amine, e.g.N,N-diethylethanamine, N-methylmorpholine,N-(1-methylethyl)-1-methylethanamine and the like. This latter reactioncan conveniently be conducted at room temperature and in some instancesat lower temperatures such as, for example, between about 0° C. and roomtemperature. The thioamide compounds of formula (I-b) can convenientlybe converted into the corresponding amides of formula (I-a) by reactionwith an oxidizing reagent such as, for example, hydrogen peroxide inwater, optionally in admixture with a reaction-inert organic co-solvent.

The compounds of formula (I) wherein R⁴ is a radical --C(═O)--NR⁵ R⁶, R⁵and R⁶ each independently being hydrogen or C₁₋₄ alkyl; said compoundsbeing represented by formula (I-c), can be prepared by reacting anappropriate amine (IX) with an aminoacid or a derivative thereof, offormula (VIII), wherein L represents a leaving group such as, forexample, hydroxy, C₁₋₆ alkyloxy, 1-H-imidazolyl, C₁₋₆ -alkyloxycarbonyl,phenoxycarbonyl or halo. ##STR8##

Said preparation of the amides of formula (I-c) can conveniently becarried out following art-known amidation and transamidation reactions.For example, said amides can be prepared by reacting an appropriatecarboxylic acid (L is OH) with an amine (IX) in the presence of areagent capable of promoting amidation reactions. Typical examples ofsuch reagents are for example dicyclohexylcarbodiimide,2-chloro-1-methylpyridinium iodide, phosphorus pentoxide,1,1'-carbonylbis[1H-imidazole], 1,1'-sulfonylbis[1H-imidazole] and thelike reagents.

Alternatively, said carboxylic acids may be converted into a suitablereactive functional derivative thereof such as, for example, an acylhalide, symmetric or mixed anhydride, ester, amide, acyl azide and thelike derivatives, before reaction with the amine of formula (IX). Saidreactive functional derivatives may be prepared following art knownmethods, for example, by reacting the carboxylic acid with ahalogenating reagent such as, for example, thionyl chloride, phosphoroustrichloride, polyphosphorous acid, phosphoryl chloride, oxalyl chlorideand the like, or by reacting said carboxylic acid with an acyl halidesuch as acetyl chloride, ethyl chloroformate and the like. The compoundsof formula (I) can also be converted into one another followingart-known functional group transformation reactions. Thus, somecompounds of formula (I) can also be useful as a precursor for othercompounds of formula (I).

For example, the N-oxide forms of the compounds of formula (I) canconveniently be prepared by N-oxidation with an appropriate organic orinorganic peroxide such as, for example, hydrogen peroxide, perbenzoicacid, 3-chloroperbenzoic acid, tert. butyl hydroperoxide and the like.Suitable solvents of said N-oxidation reactions are, for example, water,alcohols, e.g. methanol, ethanol and the like, halogenated hydrocarbons,e.g. dichloromethane, trichloromethane and the like. The compounds offormula (I) wherein R⁵ and R⁶ are hydrogen can be converted intocompounds of formula (I) wherein R⁵ and/or R⁶ are C₁₋₄ alkyl byart-known alkylation procedures.

The compounds of this invention have at least one asymmetric carbon atomin their structure, namely the carbon atom beating the R⁴ group. Saidchiral center and any other chiral center which may be present, can beindicated by the stereochemical descriptors R and S.

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereoisomersmay be separated by physical methods such as selective crystallizationand chromatographic techniques, e.g. counter current distribution,liquid chromatography and the like. Pure stereochemically isomeric formsmay also be derived from the corresponding pure stereochemicallyisomeric forms of the appropriate starting materials, provided that thereactions occur stereospecifically. Preferably, if a specificstereoisomer is desired, said compound will be synthesized bystereospecific methods of preparation. These methods will advantageouslyemploy enantiomerically pure starting materials. Stereochemicallyisomeric forms of the compounds of formula (I) are obviously intended tobe included within the scope of the invention.

The compounds of formula (I) as prepared in the above describedprocesses are generally racemic mixtures of enantiomers which can beseparated from one another following art-known resolution procedures.The racemic compounds of formula (I) which are sufficiently basic may beconverted into the corresponding diastereomeric salt forms by reactionwith a suitable chiral acid. Said diastereomeric salt forms aresubsequently separated, for example, by selective or fractionalcrystallization and the enantiomers are liberated therefrom by alkalineor acidic hydrolysis.

An interesting manner of separating the enantiomeric forms of thecompounds of formula (I) involves liquid chromatography using a chiralstationary phase such as suitably derivatized cellulose, for example,tri(dimethylcarbamoyl)cellulose (Chiracel OD®) and similar chiralstationary phases.

As an alternative to the above-mentioned resolution of the compounds offormula (I), there should be mentioned also the resolution of racemicintermediates. Particularly useful intermediates for this purpose arethe aminoacid derivatives of formula (VIII), wherein L is hydroxy, saidcompounds being represented by formula (VIII-a). ##STR9##

The aminoacids of formula (VIII-a) can conveniently be resolved byformation of the corresponding diastereomeric salt forms by reactionwith a suitable chiral base such as chiral amines, e.g.α-methylbenzylamine, cinchonine and other alkaloid bases. Obviously,said aminoacids may also be resolved by liquid chromatography using anappropriate chiral stationary phase.

The enantiomeric forms of the aminoacids of formula (VllI-a) areconverted into the enantiomeric forms of the compounds of formula (I-a)according to the procedures described hereinbefore for converting theintermediates of formula (VIII) into the compounds of formula (I).

A number of the intermediates and starting materials employed in theforegoing preparations are known compounds which can be preparedaccording to art-known methodologies of preparing said or similarcompounds. Some intermediates are less common or are novel, and a numberof preparation methods will therefore be described hereinafter in moredetail.

The intermediates of formula (II), wherein R⁴ is a radical --C(═X)--NR⁵R⁶ wherein X is O or S, R⁵ and R⁶ are hydrogen; said compounds beingrepresented by (II-a) when X is O and by (II-b) when X is S, can beprepared by reacting the corresponding nitriles of formula (X), with areagent H₂ X (VII), namely water or hydrogen sulfide, under appropriateconditions as described hereinabove for the formation of the compoundsof formula (I-a) and (I-b). ##STR10##

The nitriles of formula (X) can be prepared by reacting an appropriatebenzaldehyde of formula (XI) with a cyanide salt, thus yielding thecyanohydrin of formula (XII), which is subsequently reacted with ammoniawith formation of intermediates of formula (X). As examples of cyanidesalts there may be mentioned alkali metal and earth alkaline metalcyanides, e.g. sodium and potassium cyanide. Suitable solvents comprise,for example, water, alcohols, e.g. methanol, ethanol and the like,carboxylic acids, e.g. acetic acid, particularly glacial acetic acid,propanoic acid and the like; or a mixture of such solvents. Theintermediate cyanohydrin (XlI) may be isolated or the reaction sequencemay be performed as a one-pot procedure, for instance by reacting thebenzaldehyde of formula (XI) with ammonium cyanide. ##STR11##

The intermediates of formula (VI), can be prepared by reacting anappropriate benzaldehyde (XI) with a heterocyclic amino derivative offormula (V) in the presence of a cyanide salt and a suitable solvent.##STR12##

As examples of cyanide salts there may be mentioned alkali metal andearth alkaline metal cyanides, e.g., sodium and potassium cyanide.Suitable solvents comprise, for example, water; alcohols, e.g. methanol,ethanol and the like, carboxylic acids, e.g. acetic acid, particularlyglacial acetic acid, propanoic acid and the like; or a mixture of suchsolvents. Said reaction is conveniently carried out by stirring at roomtemperature and, if desired, slightly heating the reactants, for examplebetween 40° C. and 60° C., in particular at about 50° C. In someinstances it is advantageous to carry out said reaction in the presenceof a metal salt such as, for example, anhydrous zinc chloride and thelike, in a non-aqueous solvent, particularly glacial acetic acid, asdescribed in Chem. Ber., 98, 3902 (1965).

An interesting alternative to the latter formation of (VI) is condensinga benzaldehyde of formula (XI) with an amine of formula (V), thusforming an intermediate imine. Said imine can subsequently be treatedwith trimethylsilylcyanide in an appropriate solvent such as, forexample, a halogenated hydrocarbon, e.g. trichloromethane,dichloromethane and the like, which yields the intermediate (VI) uponwork-up.

The compounds of formula (I) show antiretroviral properties, inparticular against Human Immunodeficiency Virus (HIV), also known asLAV, HTLV-III or ARV, which is the etiological agent of Acquired ImmuneDeficiency Syndrome (AIDS) in humans. The HIV virus preferentiallyinfects human T-4 cells and destroys them or changes their normalfunction, particularly the coordination of the immune system. As aresult, an infected patient has an everdecreasing number of T-4 cells,which moreover behave abnormally. Hence, the immunological defensesystem is unable to combat infections and neoplasms and the HIV infectedsubject usually dies by opportunistic infections such as pneumonia, orby cancers. Other conditions associated with HIV infection includethrombocytopaenia, Kaposi's sarcoma and infection of the central nervoussystem characterized by progressive demyelination, resulting in dementiaand symptoms such as, progressive dysarthria, ataxia and disorientation.HIV infection further has also been associated with peripheralneuropathy, progressive generalized lymphadenopathy (PGL) andAIDS-related complex (ARC).

Due to their antiretroviral properties, particularly their anti-HIVproperties, especially their anti-HIV-1-activity, the compounds offormula (I), their pharmaceutically acceptable salts and thestereochemically isomeric forms thereof, are useful in the treatment ofindividuals infected by HIV and for the prophylaxis of individuals. Ingeneral, the compounds of the present invention may be useful in thetreatment of warm-blooded animals infected with viruses whose existenceis mediated by, or depends upon, the enzyme reverse transcriptase.Conditions which may be prevented or treated with the compounds of thepresent invention, especially conditions associated with HIV and otherpathogenic retroviruses, include AIDS, AIDS-related complex (ARC),progressive generalized lymphadenopathy (PGL), as well as chronic CNSdiseases caused by retroviruses, such as, for example HIV mediateddementia and multiple sclerosis.

Additionaly, it has been found that also the intermediates of formula(VI) show antiretroviral properties, in particular against HIV andespecially against HIV-1.

The subject compounds may be formulated into various pharmaceuticalforms for administration purposes. As appropriate compositions there maybe cited all compositions usually employed for systemically or topicallyadministering drugs. To prepare the pharmaceutical compositions of thisinvention, an effective mount of the particular compound, optionally inacid-addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirable in unitary dosage form suitable,particularly, for administration orally, rectally, percutaneously, or byparenteral injection. For example, in preparing the compositions in oraldosage form, any of the usual pharmaceutical media may be employed suchas, for example, water, glycols, oils, alcohols and the like in the caseof oral liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules, and tablets. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit forms, in which case solid pharmaceutical carriers areobviously employed. For parenteral compositions, the carrier willusually comprise sterile water, at least in large part, though otheringredients, for example, to aid solubility, may be included. Injectablesolutions, for example, may be prepared in which the carrier comprisessaline solution, glucose solution or a mixture of saline and glucosesolution. Injectable suspensions may also be prepared in which caseappropriate liquid carriers, suspending agents and the like may beemployed. Also included are solid form preparations which are intendedto be converted, shortly before use, to liquid form preparations. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewetting agent, optionally combined with suitable additives of any naturein minor proportions, which additives do not introduce a significantdeleterious effect on the skin. As appropriate compositions for topicalapplication there may be cited all compositions usually employed fortopically administering drugs, e.g., creams, jellies, dressings,shampoos, tinctures, pastes, ointments, salves, powders and the like.Application of said compositions may be by aerosol e.g. with apropellent such as nitrogen, carbon dioxide, a freon, or without apropellent such as a pump spray, drops, lotions, or a semisolid such asa thickened composition which can be applied by a swab. In particularcompositions, semisolid compositions such as salves, creams, jellies,ointments and the like will conveniently be used.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such dosage unit forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, injectable solutions or suspensions and the like, andsegregated multiples thereof.

Those of skill in the treatment of HIV-infection could easily determinethe effective daily amount from the test results presented here. Ingeneral it is contemplated that an effective daily amount would be from0.01 mg/kg to 50 mg/kg body weight, more preferably from 0.1 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 1 to 1000 mg, and in particular 5 to 200mg of active ingredient per unit dosage form.

It is evident that said effective daily amount may be lowered orincreased depending on the response of the treated subject and/ordepending on the evaluation of the physician prescribing the compoundsof the instant invention. The effective daily amount ranges mentionedhereinabove are therefore guidelines only and are not intended to limitthe scope or use of the invention to any extent.

The following examples are intended to illustrate and not to limit thescope of the present invention.

Experimental part

A. Preparation of the intermediates

Example 1

a) To a stirred and cooled suspension of 438 g of2,6-dichlorobenzaldehyde in 2000 g of glacial acetic acid there wasadded dropwise a solution of 203 g of potassium cyanide in 350 g ofwater, keeping the temperature below 25° C. Stirring was continuedovernight at room temperature. The reaction mixture was concentrated andthe residue, which solidified upon cooling, was filtered off and dried,yielding 438 g of (±)-2,6-dichloro-α-hydroxybenzeneacetonitrile; mp. 90°C. (interm. 1).

b) To a cooled (ice-bath) amount of 400 g of methanol saturated with NH₃there were added 38 g of intermediate (1). The whole was stirred for 4hours at reflux temperature and then left overnight to cool to roomtemperature. The reaction mixture was dried, filtered and evaporated.The residue was converted into the hydrochloride salt in1,1'-oxybisethane by addition of 2-propanol saturated with HCl. Thesolvent was decanted and the oily residue was successively stirred in1,1'-oxybisethane and in 2-propanone. The crystallized product wasfiltered off and dried, yielding 24.3 g of(±)-α-amino-2,6-dichlorobenzeneacetonitrile monohydrochloride; mp. >300°C. (interm. 2).

c) To a stirred and cooled amount of 450 g of concentrated sulfuric acidthere were added 23 g of intermediate (2). Stirring was continuedovernight at room temperature. The reaction mixture was poured into 2000g of ice-water and the whole was basified with ammonia. The product wasextracted with trichloromethane and the extract was dried, filtered andevaporated. The residue was crystallized from 240 g of 2-propanol at-20° C. The product was filtered off, washed with 2-propanol andpetroleumether and dried, yielding 13.5 g of(±)-α-amino-2,6-dichlorobenzeneacetamide; mp. 166.3° C. (interm. 3).

Example 2

A mixture of 2,6-dichlorobenzaldehyde (0.012 mol) and3-amino-2-pyridinone (0.01 mol) in acetic acid (50 ml) was stirred for30 rain at room temperature. Potassium cyanide (0.012 mol) was added andthe reaction mixture was stirred for 8 hours at room temperature. Thereaction mixture was poured out into water (500 ml). The resultingprecipitate was filtered off, washed with water and recrystallized fromacetonitrile. The crystals were filtered off and dried, yielding: 1.1 gof(±)-2,6-dichloro-α-[(1,2-dihydro-2-oxo-3-pyridinyl)amino]benzeneacetonitrile(37.9%); mp. 213.3° C. (interm. 4).

B. Preparation of the final compounds

Example 3

A mixture of 2 g of intermediate (3), 1.74 g of 2-chloro-3-nitropyridineand a few drops of N,N-dimethylacetamide was stirred for 1/2 hour at120° C. After cooling, the reaction mixture was purified by columnchromatography (silica gel; CH₂ Cl₂ /CH₃ OH(NH₃) 97:3). The eluent ofthe desired fraction was evaporated and the residue was crystallizedfrom acetonitrile. The product was filtered off and dried, yielding 0.8g (25.5%) of(±)-2,6-dichloro-α-[(3-nitro-2-pyridinyl)amino]benzeneacetamide; mp.207.2° C. (comp. 1).

Example 4

Intermediate (4) (0.007 mol) was dissolved in a mixture of ethanol (40ml) and a sodium hydroxide solution 2N (10 ml). A solution of hydrogenperoxide solution 30% (3.5 ml) in ethanol (5 ml) was added dropwise at5° C. The reaction mixture was stirred for 60 minutes at roomtemperature. The reaction mixture was extracted three times with CH₂Cl₂. The organic layer was separated, dried (MgSO₄), filtered and thesolvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent: CH₂ Cl₂ /(CH₃ OH/H₃) 90/10). Thepure fractions were collected and the solvent was evaporated. Theresidue was crystallized from 2-propanol. The crystals were filtered offand dried. Yielding: 1.1 g(±)-2,6-dichloro-α-[(1,2-dihydro-2-oxo-3-pyridinyl)amino]benzeneacetamide(27.5%). This fraction was recrystallized from CH₃ OH. The crystals werefiltered off and dried, yielding 0.24 g(±)-2,6-dichloro-α-[(1,2-dihydro-2-oxo-3-pyridinyl)amino]benzeneactetamide(11%)(comp. 8).

Example 5

A mixture of 2,6-dichloro-α-methylbenzenemethanamine (0.03 mol) and2-chloro-3-pyridinecarbonitrile (0.03 mol) in N,N-dimethylacetamide (fewdrops) was stirred for 20 hours at 90° C. The reaction mixture wascooled and poured out into aqueous ammonia. The mixture was extractedtwice with CH₂ Cl₂. The organic layer was separated, washed with water,dried (MgSO₄), filtered and the solvent was evaporated. The residue waspurified by column chromatography over silica gel (eluent: CH₂ Cl₂/hexane 50/50). The pure fractions were collected and the solvent wasevaporated, yielding 3.6 g(±)-2-[[1-(2,6-dichlorophenyl)ethyl]amino]-3-pyridinecarbonitrile(41.4%); mp. 84.4° C. (comp. 9).

Example 6

A mixture of 2,6-dichloro-α-methylbenzenemethanamine (0.01 mol) and1-(2-chloro-3-pyridinyl)ethanone (0.01 mol) in a mixture of ethanol andwater (1/1) (60 ml) was stirred in an autoclave for 18 hours at 150° C.The reaction mixture was cooled and diluted with water. This mixture wasextracted twice with CH₂ Cl₂. The organic layer was separated, washedwith water, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue was purified by column chromatography over silica gel (eluent:CH₂ Cl₂ /hexane 50/50). The pure fractions were collected and thesolvent was evaporated. The residue (0.5 g) was crystallized from2,2'-oxybispropane. The crystals were filtered off and dried. Yielding:0.28 g(±)-1-[2-[[1-(2,6-dichlorophenyl)ethyl]amino]-3-pyridinyl]ethanone (9%);mp. 136.2° C. (comp. 11).

The following compounds of formula (l) were prepared:

                  TABLE 1                                                         ______________________________________                                         ##STR13##                                                                    Comp. no.                                                                             Ex. No.  NHHet            Physical data                               ______________________________________                                        1       3                                                                                       ##STR14##       207.2° C.                            2       3                                                                                       ##STR15##       212.2° C.                            3       3                                                                                       ##STR16##       200.3° C.                            4       6                                                                                       ##STR17##       233.9° C.                            5       3                                                                                       ##STR18##       229.6° C.                            6       3                                                                                       ##STR19##       160.2° C.                            7       6                                                                                       ##STR20##       213.6° C.                            8       4                                                                                       ##STR21##       251.9° C.                            ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                         ##STR22##                                                                    Comp.  Ex.                            Physical                                no.    No.    R.sup.4  NHHet          data                                    ______________________________________                                         9     5      CH.sub.3                                                                                ##STR23##      84.4° C.                        10     5      CH.sub.3                                                                                ##STR24##                                             11     6      CH.sub.3                                                                                ##STR25##     136.2° C.                        12     6      CH.sub.3                                                                                ##STR26##      93.1° C.                        13     6      CH.sub.3                                                                                ##STR27##     105.0° C.                        14     6      CH.sub.3                                                                                ##STR28##     155.0° C.                        ______________________________________                                    

C. Pharmacological example

Example 7

A rapid, sensitive and automated assay procedure was used for thein-vitro evaluation of anti-HIV agents. An HIV-1 transformed T4-cellline, MT-4, which was previously shown (Koyanagi et al., Int. J. Cancer,36, 445-451, 1985) to be highly susceptible to and permissive for HIVinfection, served as the target cell line. Inhibition of the HIV-inducedcytopathic effect was used as the end point. The viability of both HIV-and mock-infected cells was assessed spectrophotometrically via thein-situ reduction of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The50% cytotoxic dose (CD₅₀ in μg/ml) was defined as the concentration ofcompound that reduced the absorbance of the mock-infected control sampleby 50%. The percent protection achieved by the compound in HIV-infectedcells was calculated by the following formula: ##EQU1## whereby(OD_(T))_(HIV) is the optical density measured with a givenconcentration of the test compound in HIV-infected cells; (OD_(C))_(HIV)is the optical density measured for the control untreated HIV-infectedcells; (OD_(C))_(MOCK) is the optical density measured for the controluntreated mock-infected cells; all optical density values weredetermined at 540 nm. The dose achieving 50% protection according to theabove formula was defined as the 50% effective dose (ED₅₀ in μg/ml). Theratio of CD₅₀ to ED₅₀ was defined as the selectivity index (SI). Thecompounds of formula (I) were shown to inhibit HIV-1 effectively.Particular values are listed in Table 1 hereinbelow.

                  TABLE 3                                                         ______________________________________                                        Comp. No.  CD.sub.50 (μg/ml)                                                                      ED.sub.50 (μg/ml)                                                                        SI                                       ______________________________________                                        1          35.8        0.03          1299                                     2          25.3        0.10          243                                      3          121.8       2             61                                       8          217.2       0.18          1181                                     7          156.7       3.8           41.5                                     11         31.4        0.068         463                                      12         3.82        0.013         289                                      13         0.24        0.0073        33                                       ______________________________________                                    

D. Composition examples

"Active ingredient (A.I.) as used throughout these examples relates to acompound of formula (I) or (VI), a pharmaceutically acceptable acidaddition salt or a stereochemically isomeric form thereof."

Example 8

Oral Drops

500 Grams of the A.I. was dissolved in 0.5 l of 2-hydroxypropanoic acidand 1.5 l of the polyethylene glycol at 60°-80° C. After cooling to30°-40° C. there were added 35 l of polyethylene glycol and the mixturewas stirred well. Then there was added a solution of 1750 grams ofsodium saccharin in 2.5 l of purified water and while stirring therewere added 2.5 l of cocoa flavor and polyethylene glycol q.s. to avolume of 50 l, providing an oral drop solution comprising 10 mg/ml ofA.I.. The resulting solution was filled into suitable containers.

Example 9

Oral Solution

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 4 l of boiling purified water. In 3l of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I.. Thelatter solution was combined with the remaining part of the formersolution and 12 l 1,2,3-propanetriol and 3 l of sorbitol 70% solutionwere added thereto. 40 Grams of sodium saccharin were dissolved in 0.5 lof water and 2 ml of raspberry and 2 ml of gooseberry essence wereadded. The latter solution was combined with the former, water was addedq.s. to a volume of 20 l providing an oral solution comprising 5 mg ofthe active ingredient per teaspoonful (5 ml). The resulting solution wasfilled in suitable containers.

Example 10

Capsules

20 Grams of the A.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 gramsmagnesium stearate were vigorously stirred together. The resultingmixture was subsequently filled into 1000 suitable hardened gelatincapsules, comprising each 20 mg of the active ingredient

Example 11

Film-Coated Tablets

Preparation of tablet core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 gramsstarch was mixed well and thereafter humidified with a solution of 5grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about200 ml of water. The wet powder mixture was sieved, dried and sievedagain. Then there was added 100 grams microcrystalline cellulose and 15grams hydrogenated vegetable oil. The whole was mixed well andcompressed into tablets, giving 10.000 tablets, each containing 10 mg ofthe active ingredient.

Coating

To a solution of 10 grams methyl cellulose in 75 ml of denaturatedethanol there was added a solution of 5 grams of ethyl cellulose in 150ml of dichloromethane. Then there were added 75 ml of dichloromethaneand 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol wasmolten and dissolved in 75 ml of dichloromethane. The latter solutionwas added to the former and then there were added 2.5 grams of magnesiumoctadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentratedcolour suspension and the whole was homogenated. The tablet cores werecoated with the thus obtained mixture in a coating apparatus.

Example 12

Injectable Solution

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 l of boiling water forinjection. After cooling to about 50° C. there were added while stirring4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of theA.I.. The solution was cooled to room temperature and supplemented withwater for injection q.s. ad 1 l, giving a solution comprising 4 mg/ml ofA.I.. The solution was sterilized by filtration (U.S.P. XVII p. 811 )and filled in sterile containers.

Example 13

Suppositories

3 Grams A.I. was dissolved in a solution of 3 grams2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 Gramssurfactant (SPAN®) and triglycerides (Witepsol 555 ®) q.s. ad 300 gramswere molten together. The latter mixture was mixed well with the formersolution. The thus obtained mixture was poured into moulds at atemperature of 37°-38° C. to form 100 suppositories each containing 30mg/ml of the A.I.

Example 14

Injectable Solution

60 Grams of A.I. and 12 grams of benzylalcohol were mixed well andsesame oil was added q.s. ad 1 l, giving a solution comprising 60 mg/mlof A.I.. The solution was sterilized and filled in sterile containers.

Example 15

2% Cream

75 mg Stearyl alcohol, 20 mg cetyl alcohol, 20 mg sorbitan monostearateand 10 mg isopropyl myristate are introduced into a doublewall jacketedvessel and heated until the mixture has completely molten. This mixtureis added to a separately prepared mixture of purified water, 200 mgpropylene glycol and 15 mg polysorbate 60 having a temperature of 70° to75° C. while using a homogenizer for liquids. The resulting emulsion isallowed to cool to below 25° C. while continuously mixing. A solution of20 mg of A.I. of formula (I), 1 mg polysorbate 80 and 637 mg purifiedwater and a solution of 2 mg sodium sulfite anhydrous in purified waterare next added to the emulsion while continuously mixing. The cream ishomogenized and filled into suitable tubes.

Example 16

Aerosols

a) To a solution of 2.5 mg A.I. in 0.7 ml of distilled water there areadded 730 μg of a 0.1 N hydrochloric acid solution. After stirring for10 minutes at room temperature, the pH of the thus obtained solution isadjusted to pH 5.5 by adding a 0.1N sodium hydroxide solution. Thenthere are added successively 4 mg of sodium chloride and 0.15 mg ofphenylmercuric acetate and the whole is stirred to produce a completesolution. Distilled water is then added to a volume of 1.0 ml. Thesolution is filled in a glass bottle closed with a mechanical pumpdelivering 0.1 ml per puff upon administration.

b) To a solution of 2 mg A.I. in 0.7 ml of distilled water there areadded 600 μg of a 0.1N hydrochloric acid solution. After stirring for 10minutes at room temperature, 10 mg of polyvinylalcohol is dissolved inthe mixture and the pH of the thus obtained solution is adjusted to pH5.5 by adding a 0.1N sodium hydroxide solution. Then there are addedsuccessively 4 mg of sodium chloride and 2 mg of phenylethyl alcohol andthe whole is stirred to produce a complete solution. Distilled water isadded to produce a volume of 1.0 ml which is filled in a glass bottleclosed with a mechanical pump spray delivering 0.1 ml per puff uponadministration.

We claim:
 1. A compound of the formula: ##STR29## a pharmaceuticallyacceptable acid addition salt form or a stereochemically isomeric formthereof, wherein:R¹ and R² each independently are halo or methyl; R³ ishydrogen, halo, nitro or trifluoromethyl; R⁴ istrifluoromethyl or methylcarbonyl; or a radical --C(═X)--NR⁵ R⁶ wherein X is O or S, and R⁵ andR⁶ each independently are hydrogen or C₁₋₄ alkyl; or a radical -Alk-R⁷,wherein Alk is C₁₋₄ alkanediyl; and R⁷ is hydrogen or hydroxy; and Hetis a heterocyclic radical of the formula: ##STR30## wherein: R¹⁴ and R¹⁵taken together form C₃₋₄ alkanediyl, and R¹³ is hydrogen or hydroxy,wherein in the heterocyclic radical (d), a nitrogen atom can optionallybe oxidized, PROVIDED THAT when the heterocyclic radical (d) is a5,6,7,8-tetrahydro-4-quinolinyl group, R¹³ is hydroxy.
 2. A compoundaccording to claim 1 wherein R⁴ is a radical C(C═O)NH₂ or methyl, andHet is 2-hydroxy-6,7-dihydro-5H-1-pyrindinyl.
 3. A compound according toclaim 2 wherein the compound is selected from the group consistingof:3-[[1-(2,6-dichlorophenyl)ethyl]amino]-6,7-dihydro-5H-1-pyrindine-2-ol;pharmaceutically acceptable salt forms thereof; and stereochemicallyisomeric forms thereof.
 4. A pharmaceutical composition comprising apharmaceutically acceptable carrier and as an active ingredient atherapeutically effective amount of a compound as defined in claim
 1. 5.A pharmaceutical composition comprising a pharmaceutically acceptablecarrier and as an active ingredient a therapeutically effective amountof a compound as defined in claim
 2. 6. A pharmaceutical compositioncomprising a pharmaceutically acceptable carrier and as an activeingredient a therapeutically effective amount of a compound as definedin claim 3.